Project Summary: The long term objective of this project is to determine if anti-angiogenic agents can increase the efficacy of radiation therapy for solid tumors. Human cancers such as soft tissue sarcomas (STS) often have areas of hypoxia secondary to irregular and porous tumor blood vessels, and hypoxia significantly reduces the efficacy of radiation therapy. Inhibition of vascular endothelial growth factor (VEGF) leads to normalization of tumor blood vessels and improvement in tumor oxygenation. Several pre-clinical studies have demonstrated potentiation of radiation therapy with anti-VEGF agents, but there is little clinical data in humans examining the role of anti-VEGF agents in this setting. Bevacizumab is a humanized anti- VEGF monoclonal antibody that binds VEGF and inhibits its activity, and clinical trials of bevacizumab have demonstrated efficacy against metastatic colorectal cancer and renal cancer. We hypothesize that bevacizumab can alter the vasculature in STS, improve tumor oxygenation, and increase the efficacy of radiation therapy. To address this hypothesis, we have designed a phase II study to examine the use of neoadjuvant radiation therapy combined with bevacizumab for patients with primary STS. The specific aims are (1) to determine the response rate of neoadjuvant bevacizumab combined with radiation therapy for intermediate and high-risk STS and (2) to analyze the biologic effects of this regimen on tumor vasculature, blood flow, and oxygenation. To accomplish these specific aims, primary tumors will be assessed for response to this regimen using RECIST criteria. Serial blood samples will be collected to measure levels of circulating angiogenic factors, and tumor biopsies before and after treatment will be analyzed for changes in VEGF and hypoxia inducible factor 1a (HIF-1a) levels, blood vessel density, and tumor expression of hypoxia-responsive and angiogenesis-related genes. Perfusion CT scans will be used to assess tumor blood flow and vascular permeability. Relevance: New biologic agents are now in development that inhibit and destroy cancers using novel mechanisms. These agents must be incorporated in clinical trials with existing treatment modalities to determine their optimal use. This study explores a novel combination of the anti-angiogenic agent bevacizumab and radiation therapy for the treatment of STS. [unreadable] [unreadable] [unreadable]